tezepelumab在严重哮喘中的基线2型生物标志物水平和反应
2022/02/28
摘要
背景：Tezepelumab是一种人单克隆抗体，可阻断胸腺基质淋巴细胞生成素(TSLP)的活性。在IIb期通路研究(NCT02054130)中，与安慰剂相比，tezepelumab显著降低了重度、不受控制哮喘成人患者的年化哮喘加重率(AAERs)。我们评估了tezepelumab在降低通路研究人群中2型(T2)炎症生物标志物水平方面的作用，以及基线T2生物标志物水平与AAERs之间的关系。
方法：患有严重、不受控制哮喘的成年人(n=550)被随机分为tezepelumab组(每4周70 mg或210 mg，或每2周280 mg)或安慰剂组，持续52周。在基线和超过52周时测定血液嗜酸性粒细胞计数、呼出一氧化氮分数(FeNO)、血清总免疫球蛋白(Ig)E、白细胞介素(IL)-5、IL-13、骨膜蛋白、胸腺和活化调节趋化因子(TARC)、TSLP。通过基线阈值(高/低)生物标志物水平分析AAERs。
结果：T2炎症生物标志物(血液嗜酸性粒细胞计数、FeNO、IL-5、IL-13和骨膜)在基线时呈正相关。在第52周，与安慰剂相比，tezepelumab 210mg治疗降低了从基线测量的所有生物标志物水平。在分别评估这些生物标志物时，无论基线血嗜酸性粒细胞计数、FeNO 或血清总 IgE、IL-5、IL-13、骨膜素、TARC 或 TSLP 水平如何，汇总的 tezepelumab 队列与安慰剂相比，急性发作减少了 55-83%。
结论：基线时，观察到T2特异性炎症生物标志物之间呈正相关。Tezepelumab降低了多个T2炎症生物标志物，这表明气道炎症降低，并减少了严重哮喘患者的病情恶化，而与基线T2生物标志物分布无关。一些患有严重哮喘的患者尽管接受了多种治疗，但仍经历了病情加重。治疗的恶化风险和异质性反应可能与对皮质类固醇反应或抵抗的特定炎症分子有关。
Baseline type 2 biomarker levels and response to tezepelumab in severe asthma
Corren J, Pham TH, Garcia Gil E, et al.
Abstract
BACKGROUND：Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER.
METHODS:Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels.
RESULTS:Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55–83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually.
CONCLUSION:At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma. Some patients with severe asthma experience exacerbations despite receiving multiple therapy. The risk of exacerbation and heterogeneous response to treatment may be associated with specific inflammatory molecules that are responsive or resistant to corticosteroids.
背景：Tezepelumab是一种人单克隆抗体，可阻断胸腺基质淋巴细胞生成素(TSLP)的活性。在IIb期通路研究(NCT02054130)中，与安慰剂相比，tezepelumab显著降低了重度、不受控制哮喘成人患者的年化哮喘加重率(AAERs)。我们评估了tezepelumab在降低通路研究人群中2型(T2)炎症生物标志物水平方面的作用，以及基线T2生物标志物水平与AAERs之间的关系。
方法：患有严重、不受控制哮喘的成年人(n=550)被随机分为tezepelumab组(每4周70 mg或210 mg，或每2周280 mg)或安慰剂组，持续52周。在基线和超过52周时测定血液嗜酸性粒细胞计数、呼出一氧化氮分数(FeNO)、血清总免疫球蛋白(Ig)E、白细胞介素(IL)-5、IL-13、骨膜蛋白、胸腺和活化调节趋化因子(TARC)、TSLP。通过基线阈值(高/低)生物标志物水平分析AAERs。
结果：T2炎症生物标志物(血液嗜酸性粒细胞计数、FeNO、IL-5、IL-13和骨膜)在基线时呈正相关。在第52周，与安慰剂相比，tezepelumab 210mg治疗降低了从基线测量的所有生物标志物水平。在分别评估这些生物标志物时，无论基线血嗜酸性粒细胞计数、FeNO 或血清总 IgE、IL-5、IL-13、骨膜素、TARC 或 TSLP 水平如何，汇总的 tezepelumab 队列与安慰剂相比，急性发作减少了 55-83%。
结论：基线时，观察到T2特异性炎症生物标志物之间呈正相关。Tezepelumab降低了多个T2炎症生物标志物，这表明气道炎症降低，并减少了严重哮喘患者的病情恶化，而与基线T2生物标志物分布无关。一些患有严重哮喘的患者尽管接受了多种治疗，但仍经历了病情加重。治疗的恶化风险和异质性反应可能与对皮质类固醇反应或抵抗的特定炎症分子有关。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校 ）
（Allergy, 2021.）
（Allergy, 2021.）
Baseline type 2 biomarker levels and response to tezepelumab in severe asthma
Corren J, Pham TH, Garcia Gil E, et al.
Abstract
BACKGROUND：Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER.
METHODS:Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels.
RESULTS:Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55–83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually.
CONCLUSION:At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma. Some patients with severe asthma experience exacerbations despite receiving multiple therapy. The risk of exacerbation and heterogeneous response to treatment may be associated with specific inflammatory molecules that are responsive or resistant to corticosteroids.
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